EDURANT (Page 5 of 9)

11 DESCRIPTION

EDURANT (rilpivirine) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). EDURANT is available as a white to off-white, film-coated, round, biconvex, 6.4 mm tablet for oral administration. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine.

The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C22 H18 N6 ∙ HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula:

Chemical Structure
(click image for full-size original)

Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range.

Each EDURANT tablet also contains the inactive ingredients croscarmellose sodium, lactose monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified microcrystalline cellulose. The tablet coating contains hypromellose 2910 6 mPa.s, lactose monohydrate, PEG 3000, titanium dioxide and triacetin.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Rilpivirine is an antiviral drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

Effects on Electrocardiogram

The effect of EDURANT at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical concern).

When doses of 75 mg once daily and 300 mg once daily of EDURANT (3 times and 12 times the dose in EDURANT) were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of EDURANT 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean Cmax observed with the recommended 25 mg once daily dose of EDURANT [see Warnings and Precautions (5.4)].

12.3 Pharmacokinetics

Pharmacokinetics in Adults

The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naïve HIV-1-infected subjects. Exposure to rilpivirine was generally lower in HIV-1 infected subjects than in healthy subjects.

Table 6: Population Pharmacokinetic Estimates of Rilpivirine 25 mg once daily in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects (Pooled Data from Phase 3 Trials through Week 96)
Parameter Rilpivirine 25 mg once dailyN = 679
AUC24h (ng∙h/mL)
Mean ± Standard Deviation 2235 ± 851
Median (Range) 2096 (198 – 7307)
C0h (ng/mL)
Mean ± Standard Deviation 79 ± 35
Median (Range) 73 (2 – 288)

Absorption and Bioavailability

After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4–5 hours. The absolute bioavailability of EDURANT is unknown.

Effects of Food on Oral Absorption

The exposure to rilpivirine was approximately 40% lower when EDURANT was taken in a fasted condition as compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal). When EDURANT was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal.

Distribution

Rilpivirine is approximately 99.7% bound to plasma proteins in vitro , primarily to albumin. The distribution of rilpivirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.

Metabolism

In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system.

Elimination

The terminal elimination half-life of rilpivirine is approximately 50 hours. After single dose oral administration of 14 C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in feces and urine, respectively. In feces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (< 1% of dose) were detected in urine.

Special Populations

Pregnancy and Postpartum

The exposure (C0h and AUC24h ) to total rilpivirine after intake of rilpivirine 25 mg once daily as part of an antiretroviral regimen was 30 to 40% lower during pregnancy (similar for the second and third trimester), compared with postpartum (see Table 7). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials. Based on the exposure-response relationship for rilpivirine, this decrease is not considered clinically relevant in patients who are virollogically suppressed. The protein binding of rilpivirine was similar (>99%) during the second trimester, third trimester, and postpartum.

Table 7: Pharmacokinetic Results of Total Rilpivirine After Administration of Rilpivirine 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy and Postpartum
Pharmacokinetics of total rilpivirine(mean ± SD, tmax : median [range]) Postpartum(6-12 Weeks)(n=11) 2nd Trimester of pregnancy(n=15) 3rd Trimester of pregnancy(n=13)
C0h , ng/mL 111 ± 69.2 65.0 ± 23.9 63.5 ± 26.2
Cmin , ng/mL 84.0 ± 58.8 54.3 ± 25.8 52.9 ± 24.4
Cmax , ng/mL 167 ± 101 121 ±45.9 123 ± 47.5
tmax , h 4.00 (2.03–25.08) 4.00 (1.00–9.00) 4.00 (2.00–24.93)
AUC24h , ng.h/mL 2714 ± 1535 1792 ± 711 1762 ± 662

Pediatric Patients

The pharmacokinetics of rilpivirine in antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years of age receiving EDURANT 25 mg once daily were comparable to those in treatment-naïve HIV-1 infected adults receiving EDURANT 25 mg once daily. There was no clinically significant impact of body weight on rilpivirine pharmacokinetics in pediatric subjects in trial C213 (33 to 93 kg).

Table 8: Population Pharmacokinetic Estimates of Rilpivirine 25 mg once daily in Antiretroviral Treatment-Naïve HIV-1-Infected Pediatric Subjects aged 12 to less than 18 years (Data from Phase 2 Trial through Week 48)
Parameter Rilpivirine 25 mg once dailyN = 34
AUC24h (ng∙h/mL)
Mean ± Standard Deviation 2424 ± 1024
Median (Range) 2269 (417 – 5166)
C0h (ng/mL)
Mean ± Standard Deviation 85 ± 40
Median (Range) 79 (7 – 202)

The pharmacokinetics and dosing recommendations of rilpivirine in pediatric patients who are less than 12 years of age and less than 35 kg have not been established [see Use in Specific Populations (8.4)].

Renal Impairment

Population pharmacokinetic analysis indicated that rilpivirine exposure was similar in HIV-1 infected subjects with mild renal impairment relative to HIV-1 infected subjects with normal renal function. No dose adjustment is required in patients with mild renal impairment. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. The potential impact is not expected to be of clinical relevance for HIV-1-infected subjects with moderate renal impairment, and no dose adjustment is required in these patients. Rilpivirine should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis [see Use in Specific Populations (8.6)].

Hepatic Impairment

Rilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. EDURANT has not been studied in subjects with severe hepatic impairment (Child-Pugh score C) [see Use in Specific Populations (8.7)].

Gender, Race, Hepatitis B and/or Hepatitis C Virus Co-infection

No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between gender, race and patients with hepatitis B and/or C-virus co-infection.

Drug Interactions

[see Contraindications (4) and Drug Interactions (7).]

Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Coadministration of EDURANT and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance. Coadministration of EDURANT and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of EDURANT with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine and to the class of NNRTIs.

EDURANT at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.

Drug interaction studies were performed with EDURANT and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. The effects of coadministration of other drugs on the Cmax , AUC, and Cmin values of rilpivirine are summarized in Table 9 (effect of other drugs on EDURANT). The effect of coadministration of EDURANT on the Cmax , AUC, and Cmin values of other drugs are summarized in Table 10 (effect of EDURANT on other drugs). [For information regarding clinical recommendations, see Drug Interactions (7).]

Table 9: Drug Interactions: Pharmacokinetic Parameters for Rilpivirine in the Presence of Coadministered Drugs
Coadministered Drug Dose/Schedule N Mean Ratio of RilpivirinePharmacokinetic ParametersWith/Without Coadministered Drug(90% CI); No Effect=1.00
Coadministered Drug Rilpivirine Cmax AUC Cmin
CI = Confidence Interval; N = maximum number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change; q.d. = once daily; b.i.d. = twice daily
*
This interaction study has been performed with a dose higher than the recommended dose for EDURANT (25 mg once daily) assessing the maximal effect on the coadministered drug.
comparison based on historic controls
Coadministration With HIV Protease Inhibitors (PIs)
Darunavir/ritonavir 800/100 mg q.d. 150 mg q.d.* 14 1.79(1.56–2.06) 2.30(1.98–2.67) 2.78(2.39–3.24)
Lopinavir/ritonavir (soft gel capsule) 400/100 mg b.i.d. 150 mg q.d.* 15 1.29(1.18–1.40) 1.52(1.36–1.70) 1.74(1.46–2.08)
Coadministration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs)
Didanosine 400 mg q.d.delayed release capsules taken 2 hours before rilpivirine 150 mg q.d.* 21 1.00(0.90–1.10) 1.00(0.95–1.06) 1.00(0.92–1.09)
Tenofovir disoproxil fumarate 300 mg q.d. 150 mg q.d.* 16 0.96(0.81–1.13) 1.01(0.87–1.18) 0.99(0.83–1.16)
Coadministration With HIV Integrase Strand Transfer Inhibitors
Cabotegravir 30 mg q.d. 25 mg q.d. 11 0.96(0.85-1.09) 0.99(0.89-1.09) 0.92(0.79-1.07)
Raltegravir 400 mg b.i.d. 25 mg q.d. 23 1.12(1.04–1.20) 1.12(1.05–1.19) 1.03(0.96–1.12)
Coadministration With other Antivirals
Simeprevir 150 mg q.d. 25 mg q.d. 23 1.04(0.95–1.13) 1.12(1.05–1.19) 1.25(1.16–1.35)
Coadministration With Drugs other than Antiretrovirals
Acetaminophen 500 mg single dose 150 mg q.d.* 16 1.09(1.01–1.18) 1.16(1.10–1.22) 1.26(1.16–1.38)
Atorvastatin 40 mg q.d. 150 mg q.d.* 16 0.91(0.79–1.06) 0.90(0.81–0.99) 0.90(0.84–0.96)
Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine 150 mg q.d.* 16 1.17(1.08–1.27) 1.25(1.16–1.35) 1.18(1.09–1.28)
Ethinylestradiol/Norethindrone 0.035 mg q.d./1 mg q.d. 25 mg q.d. 15
Famotidine 40 mg single dose taken 12 hours before rilpivirine 150 mg single dose * 24 0.99(0.84–1.16) 0.91(0.78–1.07) N.A.
Famotidine 40 mg single dose taken 2 hours before rilpivirine 150 mg single dose * 23 0.15(0.12–0.19) 0.24(0.20–0.28) N.A.
Famotidine 40 mg single dose taken 4 hours after rilpivirine 150 mg single dose * 24 1.21(1.06–1.39) 1.13(1.01–1.27) N.A.
Ketoconazole 400 mg q.d. 150 mg q.d.* 15 1.30(1.13–1.48) 1.49(1.31–1.70) 1.76(1.57–1.97)
Methadone 60-100 mg q.d., individualized dose 25 mg q.d. 12
Omeprazole 20 mg q.d. 150 mg q.d.* 16 0.60(0.48–0.73) 0.60(0.51–0.71) 0.67(0.58–0.78)
Rifabutin 300 mg q.d. 25 mg q.d. 18 0.69(0.62–0.76) 0.58(0.52–0.65) 0.52(0.46–0.59)
Rifabutin 300 mg q.d. 50 mg q.d. 18 1.43(1.30–1.56) 1.16(1.06–1.26) 0.93(0.85–1.01)
(reference arm for comparison was 25 mg q.d. rilpivirine administered alone)
Rifampin 600 mg q.d. 150 mg q.d.* 16 0.31(0.27–0.36) 0.20(0.18–0.23) 0.11(0.10–0.13)
Sildenafil 50 mg single dose 75 mg q.d.* 16 0.92(0.85–0.99) 0.98(0.92–1.05) 1.04(0.98–1.09)
Table 10: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of EDURANT
Coadministered Drug Dose/Schedule N Mean Ratio of Coadministered DrugPharmacokinetic ParametersWith/Without EDURANT(90% CI); No Effect = 1.00
Coadministered Drug Rilpivirine Cmax AUC Cmin
CI = Confidence Interval; N = maximum number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change; q.d. = once daily; b.i.d. = twice daily
*
This interaction study has been performed with a dose higher than the recommended dose for EDURANT (25 mg once daily) assessing the maximal effect on the coadministered drug.
AUC(0–last)
N (maximum number of subjects with data) for AUC(0–∞) = 15
Coadministration With HIV Protease Inhibitors (PIs)
Darunavir/ritonavir 800/100 mg q.d. 150 mg q.d.* 15 0.90(0.81–1.00) 0.89(0.81–0.99) 0.89(0.68–1.16)
Lopinavir/ritonavir(soft gel capsule) 400/100 mg b.i.d. 150 mg q.d.* 15 0.96(0.88–1.05) 0.99(0.89–1.10) 0.89(0.73–1.08)
Coadministration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs)
Didanosine 400 mg q.d.delayed release capsules taken 2 hours before rilpivirine 150 mg q.d.* 13 0.96(0.80–1.14) 1.12(0.99–1.27) N.A.
Tenofovir disoproxil fumarate 300 mg q.d. 150 mg q.d.* 16 1.19(1.06–1.34) 1.23(1.16–1.31) 1.24(1.10–1.38)
Coadministration With HIV Integrase Strand Transfer Inhibitors
Cabotegravir 30 mg q.d. 25 mg q.d. 11 1.05 (0.96-1.15) 1.12 (1.05-1.19) 1.14 (1.04-1.24)
Raltegravir 400 mg b.i.d. 25 mg q.d. 23 1.10(0.77–1.58) 1.09(0.81–1.47) 1.27(1.01–1.60)
Coadministration With other Antivirals
Simeprevir 150 mg q.d. 25 mg q.d. 21 1.10(0.97–1.26) 1.06(0.94–1.19) 0.96(0.83–1.11)
Coadministration With Drugs other than Antiretrovirals
Acetaminophen 500 mg single dose 150 mg q.d.* 16 0.97(0.86–1.10) 0.91(0.86–0.97) N.A.
Atorvastatin 40 mg q.d. 150 mg q.d.* 16 1.35(1.08–1.68) 1.04(0.97–1.12) 0.85(0.69–1.03)
2-hydroxy-atorvastatin 16 1.58(1.33–1.87) 1.39(1.29–1.50) 1.32(1.10–1.58)
4-hydroxy-atorvastatin 16 1.28(1.15–1.43) 1.23(1.13–1.33) N.A.
Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine 150 mg q.d.* 16 0.98(0.85–1.13) 1.03(0.95–1.13) N.A.
Digoxin 0.5 mg single dose 25 mg q.d. 22 1.06(0.97–1.17) 0.98(0.93–1.04) N.A.
Ethinylestradiol 0.035 mg q.d. 25 mg q.d. 17 1.17(1.06–1.30) 1.14(1.10–1.19) 1.09(1.03–1.16)
Norethindrone 1 mg q.d. 17 0.94(0.83–1.06) 0.89(0.84–0.94) 0.99(0.90–1.08)
Ketoconazole 400 mg q.d. 150 mg q.d.* 14 0.85(0.80–0.90) 0.76(0.70–0.82) 0.34(0.25–0.46)
R(-) methadone 60–100 mg q.d., individualized dose 25 mg q.d. 13 0.86(0.78–0.95) 0.84(0.74–0.95) 0.78(0.67–0.91)
S(+) methadone 13 0.87(0.78–0.97) 0.84(0.74–0.96) 0.79(0.67–0.92)
Metformin 850 mg single dose 25 mg q.d. 20 1.02(0.95–1.10) 0.97(0.90–1.06) N.A.
Omeprazole 20 mg q.d. 150 mg q.d.* 15 0.86(0.68–1.09) 0.86(0.76–0.97) N.A.
Rifampin 600 mg q.d. 150 mg q.d.* 16 1.02(0.93–1.12) 0.99(0.92–1.07) N.A.
25-desacetylrifampin 16 1.00(0.87–1.15) 0.91(0.77–1.07) N.A.
Sildenafil 50 mg single dose 75 mg q.d.* 16 0.93(0.80–1.08) 0.97(0.87–1.08) N.A.
N -desmethyl-sildenafil 16 0.90(0.80–1.02) 0.92(0.85–0.99) N.A.

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